Radiotherapy–immunotherapy combinations – perspectives and challenges

Abstract

Ionizing radiation has historically been used to treat cancer by killing tumour cells, in particular by inducing DNA damage. This view of radiotherapy (RT) as a simple cytotoxic agent has dramatically changed in recent years, and it is now widely accepted that RT can deeply reshape the tumour environment by modulating the immune response. Such evidence gives a strong rationale for the use of immunomodulators to boost the therapeutic value of RT, introducing the era of ‘immunoradiotherapy’. The increasing amount of preclinical and clinical data concerning the combination of RT with immunomodulators, in particular with immune checkpoint inhibitors such as anti‐PD‐1/PD‐L1 and anti‐CTLA4, reflects the interest of the scientific and medical community concerning immunoradiotherapy. The expectations are enormous since the rationale for performing such combinations is strong, with the possibility to use a local treatment such as RT to amplify a systemic antitumour response, as illustrated by the case of the abscopal effect. Nevertheless, several points remain to be addressed such as the need to find biomarkers to identify patients who will benefit from immunoradiotherapy, the identification of the best sequences/schedules for combination with immunomodulators and mechanisms to overcome resistance. Additionally, the effects of immunoradiotherapy on healthy tissues and related toxicity remain largely unexplored. To answer these critical questions and make immunoradiotherapy keep its promising qualities, large efforts are needed from both the pharmaceutical industry and academic/governmental research. Moreover, because of the work of both these entities, the arsenal of available immunomodulators is quickly expanding, thus opening the field to increasing combinations with RT. We thus forecast that the field of immunoradiotherapy will further expand in the coming years, and it needs to be supported by appropriate investment plans.

Towards a cancer mission in Horizon Europe: recommendations

“…Immunological interventions with checkpoint inhibitors, antibodies, vaccination programmes and cell therapies show ample promise [36][37][38][39][40]. In addition, developments in radiobiology and radiophysics have boosted innovation in radiation therapies; for example, novel fractionated radiation regimens, use of different sources (photons, protons and light ions), or combination with other treatments offer new perspectives [41][42][43][44][45]. Surgical treatment is moving towards technologies with improved preservation of organ function and integration with both radiation therapy and medical anticancer treatment [41,46].…”

Technology‐driven research for radiotherapy innovation

“…As largely debated in the current thematic issue of Molecular Oncology, radiation oncology is a crucial player for the rapid transformation of oncology toward personalized and precision care (Baumann et al, 2016;Krause et al, 2020;Mondini et al, 2020). Among the curative options, it is the only that can merge its increasing 'surgical' ability with the potential of sterilizing nodes suspected of infiltration of tumor cells; in addition, the combination with immunotherapy is also expected to extend radiotherapy as a primary player for the ambitious aim of caring (or preventing) metastatic disease (Kroeze et al, 2017).…”

Exosomal PD-L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies

“…The abscopal effect refers to that treatment of a local tumor leads to the regression of distant tumors (Postow et al, 2012;Demaria and Formenti, 2020;Fionda et al, 2020;Mondini et al, 2020).…”